One night of sleep deprivation during the early morning hours (PSD: patient awake 0200-2100 hours) produces an acute, but transient antidepressant response in over 60% of bipolar subjects. Until recently, PSD has shown little clinical utility because its effects wane within 48 hours. However, four studies have now documented that concurrent lithium treatment maintains the acute antidepressants effects of sleep deprivation indefinitely, void of heterocyclic-induced mania risk. While effective, sleep deprivation is cumbersome; patients are often skeptical and persuading them to undergo it, or continue with it once begun, is difficult. If, however we understood the mediating factors, we might be able to bypass sleep deprivation and administer the mediator instead. The hypothalamic-thyroid axis (HPT) may be such a mediator. Nocturnal TSH secretion is reduced in bipolar depression and normalizes with successful treatment. PSD increases TSH and increases in TSH levels during sleep deprivation correlate with antidepressant effect. TRH produces an acute, but transient, antidepressant effect in patients with depression. The similarities between the descriptions of the acute, but transient, antidepressant effects of PSD and TRH are striking. We postulate that the antidepressant effects of sleep deprivation are due to HPT stimulation at the level of the hypothalamus or pituitary. We will administer TRH or placebo during the early morning hours to bipolar depressed subjects to determine effects on TSH, mood, and motor activity. We predict that TRH will increase nocturnal TSH levels and produce same-day, but short-term, increases in mood and locomotion. We hope to use the data derived from this study as initial data for developing a prospective study of the HPT axis, antidepressant, and locomotor effects of lithium/PSD and lithium/TRH in bipolar illness.